Organization of the autophagy pathway in neurons

Sidibe, David; Vogel, Maria C.; Maday, Sandra

doi:10.1016/j.conb.2022.102554

Cited by 22 publications

(11 citation statements)

References 111 publications

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“…Autophagosomes and endosomes regulate the axonal proteome by transporting cargos from the distal axon to the soma for degradation in lysosomes (Winckler et al, 2018;Sidibe et al, 2022). The degree of overlap between these pathways, however, is poorly understood.…”

Section: Retrograde Autophagosomes Do Not Carry Newly Endocytosed Cargosmentioning

confidence: 99%

“…Autophagy and endocytic trafficking are two key pathways that regulate the composition and integrity of the neuronal proteome (Winckler et al, 2018;Sidibe et al, 2022). Dysfunction in autophagic and endolysosomal trafficking is linked to many neurodevelopmental and neurodegenerative diseases (Winckler et al, 2018;Malik et al, 2019;Sidibe et al, 2022). But how autophagy and endocytic pathways are organized in the context of neurons to maintain protein and organelle homeostasis is a major area of investigation.…”

Section: Introductionmentioning

confidence: 99%

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Retrograde Axonal Autophagy and Endocytic Pathways Are Parallel and Separate in Neurons

Kulkarni

Stempel²,

Anand³

et al. 2022

J. Neurosci.

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Autophagy and endocytic trafficking are two key pathways that regulate the composition and integrity of the neuronal proteome. Alterations in these pathways are sufficient to cause neurodevelopmental and neurodegenerative disorders. Thus, defining how autophagy and endocytic pathways are organized in neurons remains a key area of investigation. These pathways share many features and converge on lysosomes for cargo degradation, but what remains unclear is the degree to which the identity of each pathway is preserved in each compartment of the neuron. Here, we elucidate the degree of intersection between autophagic and endocytic pathways in axons of primary neurons. Using microfluidic chambers, we labeled newly-generated bulk endosomes and signaling endosomes in the distal axon, and systematically tracked their trajectories, molecular composition, and functional characteristics relative to autophagosomes. We find that newly-formed endosomes and autophagosomes both undergo retrograde transport in the axon, but as distinct organelle populations. Moreover, these pathways differ in their degree of acidification and association with molecular determinants of organelle maturation. These results suggest that the identity of autophagic and newly endocytosed organelles is preserved for the length of the axon. Lastly, we find that expression of a pathogenic form of -synuclein, a protein enriched in presynaptic terminals, increases merging between autophagic and endocytic pathways. Thus, aberrant merging of these pathways may represent a mechanism contributing to neuronal dysfunction in Parkinson's disease and related -synucleinopathies.

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Section: Retrograde Autophagosomes Do Not Carry Newly Endocytosed Cargosmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Retrograde Axonal Autophagy and Endocytic Pathways Are Parallel and Separate in Neurons

Kulkarni

Stempel²,

Anand³

et al. 2022

J. Neurosci.

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“…By contrast, defects in autophagic flux lead to accumulation of structures with both GFP and mCherry fluorescence (Klionsky et al, 2021). We examined this flux in motor neuron cell bodies, where mature autolysosomes are predicted to accumulate (Sidibe et al, 2022). In wild-type animals we observed mCherry-positive/GFP-negative puncta reflecting mature autolysosomes.…”

Section: Resultsmentioning

confidence: 99%

ESCRT disruption provides evidence against signaling functions for synaptic exosomes

Dresselhaus

Harris

Koles

et al. 2023

Preprint

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Exosomes are membrane-bound vesicles released by many cells including neurons, carrying cargoes involved in signaling and disease. It has been unclear whether exosomes promote intercellular signaling in vivo or serve primarily to dispose of unwanted cargo. This is because manipulations of exosome cargo expression or traffic often result in their depletion from the donor cell, making it difficult to distinguish whether these cargoes act cell-autonomously or through transcellular transfer. Exosomes arise when multivesicular endosomes fuse with the plasma membrane, releasing their intralumenal vesicles outside the cell. We show that loss of multivesicular endosome-generating ESCRT (endosomal sorting complex required for transport) machinery disrupts release of exosome cargoes from Drosophila motor neurons, without depleting them from the donor presynaptic terminal. Cargoes and autophagic vacuoles accumulate in presynaptic terminals, suggesting that compensatory autophagy follows endosome dysfunction. Surprisingly, exosome cargoes Synaptotagmin-4 (Syt4) and Evenness Interrupted (Evi) retain many of their signaling activities upon ESCRT depletion, despite being trapped in presynaptic terminals. Thus, these cargoes may not require intercellular transfer, and instead are likely to function cell autonomously in the motor neuron. Our results indicate that synaptic exosome release depends on ESCRT, and serves primarily as a proteostatic mechanism for at least some cargoes.

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“…It should be mentioned that for autophagy of neurons, both protective and pathological functions are possible [27,28]. The role of autophagy after spinal cord injury is complex and heterogeneous, and it may change over time [27][28][29]. For example, autophagy may help clear damaged cells and maintain energy metabolism in the early stages of trauma; In the later stage, they may participate in axonal regeneration and repair [29,30].…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis based on machine learning algorithm: Hspb1 and Lgals3 in neurons after spinal cord injury are closely related to autophagy

Yan

et al. 2023

Preprint

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Spinal cord injury (SCI) refers to the dysfunction of sensorimotor and autonomic nerves caused by extensive and permanent loss of neurons after different degrees of damage to the spinal cord or cauda equina. The mechanism of spinal cord neuron injury after SCI has not been fully elucidated so far, although some opinions have been put forward. In this study, we extracted primary spinal neurons from neonatal rats, constructed a neuron injury model using glutamate stimulation, and performed full transcriptome sequencing analysis. We used machine learning algorithm (WGCNA, RF, and LASSO) to comprehensively and in-depth explore the important genes of spinal cord neuron injury and screen out the key genes Anxa2, Ccng1, Hspb1, Lgals3, Timp1 and S100a10, which are accompanied by the up-regulation of six expression levels of spinal cord neuron injury. Importantly, Hspb1 and Lgals3 are closely related to autophagy. To improve the reliability of our results, we downloaded the corresponding expression levels of six key genes of GSE2599, GSE20907, GSE45006, and GSE174549 to make ROC curve for verification, and then conducted RT-PCR verification of six key genes in vitro and in vivo, respectively. These findings will help us to further understand the pathogenesis of SCI, and may contribute to the screening of key targets for future clinical treatment.

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Organization of the autophagy pathway in neurons

Cited by 22 publications

References 111 publications

Retrograde Axonal Autophagy and Endocytic Pathways Are Parallel and Separate in Neurons

Retrograde Axonal Autophagy and Endocytic Pathways Are Parallel and Separate in Neurons

ESCRT disruption provides evidence against signaling functions for synaptic exosomes

Comprehensive analysis based on machine learning algorithm: Hspb1 and Lgals3 in neurons after spinal cord injury are closely related to autophagy

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